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MULTIFACTORIAL INHERITANCE

MULTIFACTORIAL INHERITANCE. Polygenic traits are controlled by two or more genes . Examples: color of skin, hair and eyes . They c ause slight and often variable range of differences throughout population.

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MULTIFACTORIAL INHERITANCE

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  1. MULTIFACTORIAL INHERITANCE

  2. Polygenic traits are controlled by two or more genes. Examples: color of skin, hair and eyes. • They cause slight and often variable range of differences throughout population.

  3. The most common cause of genetic disorders is multifactorial or polygenic inheritance. Traits that are due to the combined effects of multiple genes are polygenic (many genes). When environmental factors also play a role in the development of a trait, the term multifactorial is used to refer to the additive effects of many genetic and environmental factors.

  4. What Is a Multifactorial Trait? • Controlled by two or more genes and affected by environmental factors • Example: Height • Interaction of genes with environment produce many different phenotypes • Multifactorial = complex traits • Most traits that vary in the population, including common human diseases with the genetic component, are complex traits

  5. Variation in Height

  6. Height as a Multifactorial Trait

  7. Characteristics of Multifactorial Traits • Several genes control trait • Not inherited as dominant or recessive • Genes controlling trait contribute a small amount to phenotype • Environmental factors interact with genes to produce phenotype

  8. Characteristics of Multifactorial Traits • There are many phenotypic differences in trait • Distributions of phenotypes form a bell-shaped curve

  9. Variation in Height

  10. How Many Genes Control Trait? • As the number of genes increases, phenotypic differences among people decreases • As differences among people increase, more likely environmental factors, affect the phenotypes together • Environmental factors for height: hormones and diet

  11. Multifactorial conditions tend to run in families, but the pattern of inheritance is not as predictable as in single gene disorders. The degree of risk of a multifactorial disorder occurring in relatives is related to the number of genes they share in common with the affected individual. The closer the degree of relationship, the more genes in common. The degree of risk also increases with the degree of severity of the disorder.

  12. Identical twins who are exactly alike genetically, do not always have the same condition when inheritance is multifactorial. This indicates that there are nongenetic factors that also play a role in the expression of multifactorial traits. For instance, the risk of coronary heart disease increases with smoking or obesity. Maternal alcohol abuse or uncontrolled diabetes increases the risk of having a child with a congenital heart defect.

  13. Empiric risks are used to predict the recurrence of a multifactorial disorder. This is a risk that is based on population studies and on mathematical models. For many multifactorial or polygenic disorders, parents who have had one affected child have a 3-5% risk in future pregnancies of having another affected child. Affected individuals have a similar risk in future generations. More distant relatives, however, have a lower recurrence risk.

  14. In conditions inherited in a multifactorial fashion, the risk may depend on the sex of the affected individual. For example, pyloric stenosis is a multifactorial disorder that occurs five times more frequently in males than in females. If a female child has pyloric stenosis, her risk and her parent's risk of having another affected child would be higher than if a male child has pyloric stenosis.

  15. Some of the most common chronic diseases are multifactorial genetic disorders. Conditions with multifactorial inheritance include many birth defects, cancers, coronary artery disease, diabetes, hypertension, and mental disorders. It explains the familial distribution of many disorders.

  16. Two close individuals in a family have more common inherited genes. • The closer the degree of relationship, the concordance of the disease increases. • The genetic contribution to the environmental impacts can be compared by the concordance of the diseases in relatives.

  17. Concordance and Discordance • If two patients are relatives and have the same disorder, these patients are concordant for this disorder. • If only one of them is affected, these patients are discordant for this disorder.

  18. Multifactorial inheritance can be analysed by 3 different techniques: A- Twin Studies B- Pedigrees C- Family Correlation

  19. Twin Studies • Dizygotic twins (DZ) don’t share the whole genetic constitution, but they share the same enviroment. So, they can be useful at the measurement of the disease concordance. • Monozygotic twins (MZ) share the same genetic constitution and the same enviroment. So, they can be useful at the comparison of the relatives in the same enviroment.

  20. Concordant: have the same traitDiscordant: do not have the same trait

  21. The prevalance of MZ twins is 0.3% in all pregnancies. • DZ twins share 50% of their genome.

  22. Concordance of Disorder in MZ Twins • This is a good way for determining the impact of genotype in the occurrence of a disorder. • If one of the MZ twins has sickle cell anemia, the other should have the disease (concordance 100%).

  23. If one of the MZ twins has DM( diabetes mellitus) Type 1, the other should have the disease in a rate of 40%. • If MZ concordance is less than 100%, it can be said that non genetical factors are also important in the occurrence of the disease. • These factors can be enviromental such as infections or diet, and also they can be somatic mutations, aging, the differences of X inactivation between twins.

  24. The Comparison of Concordance in MZ and DZ Twins • MZ and DZ twins share the same intrauterine atmosphere and usually they are grown up in their family with their parents. • Concordance is higher in MZ than DZ twins, so genetic factors are important in MZ twins.

  25. Aspects of Multifactorial Inheritance • 1- Complex Traits: Traits such as intelligence, behavioural traits, height and weight approximate to a normal distribution in the general population. A large number of genes are involved in determining these characteristics together with enviromental factors. For example, factors influcing height include parental height, nutrition and chronic illness.

  26. 2- Falconer’s polygenic threshold model: This is based on the idea that; liability to a condition is multifactorial and follows a normal distribution in the general population and that the disease occurs when a particular threshold value is exceeded. • The normal distribution for liability is shifted in close relatives of an affected individual; hence a greater proportion of them will exceed the critical threshold value and be affected. For first degree relatives, the expected incidence approximate to the square-root of the population incidence.

  27. For a condition affecting 1/1000 individuals (0.1%), the risk to sibs, parents and children is ~1/30 (3%), falling to 1/100 (1%) for second-degree relatives and close to population risk for third-degree relatives.

  28. 3- Gender Predisposition: For most multifactorial disorders, males or females have a greater frequency. If the disorder does occur in the less likely gender then there is a greater recurrence risk implying more genes and/or enviromental factors are present in that family.

  29. Measurement of Familial Cluster • Relative Risk λr • The familial cluster of a disorder can be measured by the comparison of the prevalance of the disease in patients’ relatives to the prevalance of the disease in general population.

  30. the prevalance of the disease in patients’ relatives (“r”) λr = ------------------------------------------------ the prevalance of the disease in general population

  31. As λr increases, familial cluster will be more. • If λr=1, then the probability of having the disease for a relative is not high from a patient in the population.

  32. Heritability (h2) • The heritability of a trait within a population is the proportion of observable differences (height,BMI,etc) in a trait between individuals within a population that is due to genetic differences. • Factors including genetics, enviroment and random chance can all contribute to the variation between individuals in their observable characteristics (in their “phenotypes"). • Heritability thus analyzes the relative contributions of differences in genetic and non-genetic factors to the total phenotypic variance in a population. For instance, some humans in a population are taller than others; heritability attempts to identify how much genetics is playing a role in part of the population being extra tall.

  33. Heritability: Twin Studies • Twin studies are often used to assess genetic effects on variation in a trait. • If the variation is basicly identified by environment, the variations of MZ and DZ twins are alike each other and h2 will be near to 0; if genetics is basic in the variation, then h2 will be 1.

  34. h2 can range from 0.0 to 1.0. If genes don’t contribute to phenotypic variations, in this situation heritability is 0 or if h2 = 0.0 it means that all of the variabilityobserved in a trait in a given population is due to environmental differences experienced by theindividuals. • If genes are totally responsible from phenotypic variations, then heritability is 1 or if h2 = 1.0, it means that all of the differencesare due to genetic differences among the people. For most continuous traits, heritability issomewhere in between.

  35. Change in Change in DZ twins – MZ twins h2 = --------------------------------------- Change in DZ twins

  36. Features of Multifactorial Inheritance

  37. 1-These are not single gene disorders and they don’t show Mendelian inheritance. 2- Familial clustering is observed.

  38. 3- The risk for the first-degree relatives (parents, siblings,offspring) approximates the square root of the population risk. For the majority of defects, the risk is 2% to 5%, which is 20 to 40 times the frequency of the problem in the general population.

  39. 4- Second degree relatives (uncles, aunts) have a clearly lower risk than first-degree relatives. 5- The greater the number of affected family members, the greater the risk for recurrence

  40. 6- Consanguinity increases the risk. 7- The more severe the malformation, the greater the risk for recurrence. 8- The risk for recurrence will be increased for relatives of the least affected gender, if gender differences are noted.

  41. 9- Concordance in twins. The frequency of concordance and discordance in MZ and DZ twins has been used to argue both for enviromental and for single gene causation of common malformations.

  42. Multifactorial Diseases Disease Incidence(1/1000) Cleft lip-palate0.4-1.7 Cleft palate0.4 Kongenital heart defects4-8 Neural tube defects 2-10 Anencephalyvariable Spina bifida variable Pyloric stenosis 1

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